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Insulin resistance usually occurs early in the development of type 2 diabetes. An altered balance in the autonomic nervous system and in certain endocrine and inflammatory pathways, might contribute to the development of insulin resistance. In diabetes, hyperglycemia further aggravates insulin resistance as well as beta cell dysfunction but the mechanisms causing this phenomenon, i.e. glucotoxicity, are not fully understood.

Insulin resistance can be demonstrated in healthy first-degree relatives of type 2 diabetes patients who also have a high risk of developing type 2 diabetes. Relatives and control subjects without family history of diabetes were studied with respect to insulin sensitivity and the activity in the autonomic nervous system (ANS) and in the cortisol axis. Levels of sex hormones, leptin and cytokines were analysed. Abdominal adipose tissue distribution was determined with computed tomography.

Male relatives had decreased testosterone levels and increased leptin levels. There was an inverse relationship between insulin sensitivity and leptin levels, and in males a positive association between insulin sensitivity and testosterone levels. A tendency to lower parasympathetic reactivity was found in the relatives using heart rate variability assessment. The sympathetic/parasympathetic ratio during stress provocation was inversely correlated to insulin sensitivity, measured with glucose clamp. The insulin-resistant subjects also exhibited an overall blunted reactivity in the ANS. Cortisol reactivity after stimulation with ACTH and CRH was lower in the relatives. The amount of visceral adipose tissue (VAT) was associated with insulin resistance and with heart rate at rest and during controlled breathing and it also correlated with heart rate and sympathetic/parasympathetic ratio after an orthostatic manoeuvre.

Type 2 diabetic subjects with good and poor glycemic control, respectively, and matched healthy control subjects were examined with respect to insulin sensitivity, cortisol axis activity and blood levels of leptin, sex hormones and the adipocyte-secreted inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Biopsies were taken from subcutaneous adipose tissue for determination of adipocyte size. Diabetes subjects were more insulin-resistant than controls and diabetics with poor control exhibited the highest degree of insulin resistance. This group also had the highest levels of TNF-α, morning serum cortisol and non-esterified fatty acids (NEFA). In correlation analyses, significant associations were seen between glycemic level and insulin resistance, TNF-α, IL- 6 and serum cortisol levels. Insulin resistance was positively correlated to NEFA levels, TNF-α and ACTH-stimulated cortisol levels. Adipocyte size was associated with insulin resistance and levels of IL-6 and leptin.

The findings support a connection between insulin resistance and VAT amount, activity in the ANS and blood levels of hormones and adipocyte-derived molecules. Dysregulation in the complex interplay between such factors may contribute to the early pathogenesis of insulin resistance and type 2 diabetes. Adipokines and the cortisol system can also potentially aggravate hyperglycemia in patients with manifest type 2 diabetes.